• Supported by the ACAR Research Award our studies aim to identify the cellular distribution of netrin-3 in the brain, determine the functional importance of these newly identified mutations, and the consequences of disrupting netrin-3 function in vivo. (mcgill.ca)
  • The same effect was seen on overexpression of two distinct neuroblastoma-associated frameshift mutations, 676delG and K155X - but not the R100L missense mutation - in the presence of endogenous Phox2b, pointing to their dominant-negative effects. (prolekarniky.cz)
  • The kat and kat2J Nek1 mutations cause pleiotropic effects, including perinatal mortality in some pups, growth retardation, facial dysmorphism, abnormalities in the choroid plexus, PKD, and early death with or from progressive renal failure. (biomedcentral.com)
  • However, both biochemical and electrophysiological results showed that the mutations did not have a dominant-negative effect on WT, indicating that the mechanism of the L413P and L559H mutations might be haploinsufficiency. (elsevierpure.com)
  • A shortage of the normal protein likely impairs the assembly of ribosomes, but the specific effects of the mutations are not known. (medlineplus.gov)
  • Importantly, I have used RNA-guided Cas9 nuclease to reverse the candidate variants to wild-type sequence thus giving me the opportunity - for the first time in any arrhythmia disease - to definitively establish the role of he mutations to the cellular phenotype in a specific patient. (grantome.com)
  • Detailed molecular characterization of two caveolin-3 mutations (P104L and ΔTFT), associated with LGMD-1C, shows them to impart a dominant-negative effect on wild-type caveolin-3, rendering it dysfunctional through sequestration in the Golgi complex. (elsevierpure.com)
  • The pleiotropic effects of TBX4 in lung disease may be in part explained by the differential effect of pathogenic mutations located in critical protein domains. (stanford.edu)
  • The positive effect of sirtuins in extending lifespan, through a mechanism that mimics caloric restriction, has been demonstrated in a wide range of organisms. (cellr4.org)
  • My PhD work focused on the cellular mechanism of a natural product as a potential therapeutic against prostate cancer. (edu.lb)
  • Mechanism of KMT5B haploinsufficiency in neurodevelopment in humans and mice. (sfari.org)
  • This cellular compartmentalization of PTEN was investigated in lung neuroendocrine tumors (lung NET). (biomedcentral.com)
  • Cellular ubiquitinylation and sumoylation likely influence the functional PTEN loss in high grade lung NET. (biomedcentral.com)
  • Cellular assays provided evidence that reduced NFκB activities due to p65 haploinsufficiency resulted in decreased differentiation and elevated apoptosis in the osteogenic cells. (unc.edu)
  • This effect on terminal differentiation is associated with an increased number of phox2b + , ascl1 + , elavl3 − cells that respond poorly to retinoic acid. (prolekarniky.cz)
  • A defining feature of neuroblastic tumors is their broad spectrum of cellular differentiation, ranging from undifferentiated cells that indicate a poor prognosis to those showing greater differentiation and predicting a generally favorable outcome [2] . (prolekarniky.cz)
  • TBX5 is a T-box containing transcription factor critical to mammalian tissue patterning and cellular differentiation during development of the upper extremities and the heart. (grantome.com)
  • Autophagy also regulates cell proliferation, differentiation, survival, and apoptosis, highlighting its role in maintaining cellular homeostasis [ 1 ]. (hindawi.com)
  • Overexpression of the orange subunits can be inconsequential from the perspective of the trimer output but entails a futile cost, whereas overexpression of the green ones leads to a titration effect (formation of dimeric subcomplexes), which reduces trimer output. (biomedcentral.com)
  • My studies of aneuploidy began as a graduate student in Dr. Mark Winey's laboratory at the University of Colorado-Boulder, where I discovered a shared localization of yeast Ndc1p to spindle poles and nuclear pore complexes and I identified NDC1 gene dosage effects - both haploinsufficiency and overexpression - that lead to genetic instability and aneuploidy in yeast. (cuanschutz.edu)
  • Finally, we provide evidence that cellular phenotypes associated with autism-linked gene haploinsufficiency can be rescued by transcriptional activation of the intact allele in vitro, offering a proof of concept for a potential therapeutic approach for ASDs. (nature.com)
  • Mice with p65 haploinsufficiency targeting osteoprogenitors were generated and the phenotypes were characterized. (unc.edu)
  • We used patient-derived fibroblasts to characterize cellular phenotypes and found a decrease of ACO2 protein levels, while ACO2 enzyme activity was not affected compared to two age- and gender-matched control lines. (huji.ac.il)
  • Thus we characterized the cellular and molecular properties of the R26Q mutant protein to better understand how this mutation can manifest as such distinct disease phenotypes. (elsevierpure.com)
  • 2021. Dissociable effects of complement C3 and C3aR on survival and morphology of adult born hippocampal neurons, pattern separation, and cognitive flexibility in male mice . (cardiff.ac.uk)
  • 2021. Analysis of diffusion tensor imaging data from the UK Biobank confirms dosage effect of 15q11.2 copy number variation on white matter and shows association with cognition . (cardiff.ac.uk)
  • Recent clinical studies report the beneficial effects of lithium treatment in several people affected with the SHANK3 gene, a highly penetrating, monogenic cause of ASD, and a leading predisposition of Phelan-McDermid Syndrome (PMS)," says Zhou. (mcgill.ca)
  • However, the specific mechanisms by which lithium exerts its behavioral-stabilizing effects under the SHANK3 haploinsufficiency have yet to be identified. (mcgill.ca)
  • In a recent conversation with Guy Rouleau, Thomas Bourgeron, and Boris Chaumette, we learned the beneficial effects of lithium in several patients with SHANK3 mutation. (mcgill.ca)
  • Most reported cases are caused by 22q13.3 deletions, leading to SHANK3 haploinsufficiency, b. (biomedcentral.com)
  • These pleiotropic effects are regulated by multiple layers of non-genetic regulation, including epigenetic silencing and post-transcriptional regulation by post-translational modifications (PTM) and non-coding RNAs [ 7 ]. (biomedcentral.com)
  • Rare genetic and genomic syndromes have provided insights into the molecular, cellular and circuit changes that underlie autism and associated developmental delay syndromes. (biomedcentral.com)
  • however, the extent to which the association between autism symptoms and epilepsy is due to shared aetiology or to the direct effects of seizures is a topi. (biomedcentral.com)
  • We also analysed the impact of CTCF haploinsufficiency by examining gene expression changes in CTCF -altered endometrial carcinoma. (preprints.org)
  • We sequenced the EDN1 untranslated regions of a small subset of patients with PAH, predicted the effect in silico, and used a luciferase assay with the different genotypes to analyze its influence on gene expression. (stanford.edu)
  • The most critical of these proteins is the signal transducer and activator of transcription 5b (STAT5b), which couples GH binding to the activation of gene expression that leads to the intracellular effects of GH, including synthesis of IGF-I, insulin-like growth factor binding protein 3 (IGFBP3), and ALS. (medscape.com)
  • Murine studies revealed that Nell-1 haploinsufficiency results in marked reductions in the numbers of Sca-1+CD45-CD31- bone marrow MPCs associated with low bone mass. (nih.gov)
  • Haploinsufficiency of Tbx5 in murine models results in diminished cardiac expression of gap junction proteins, atrial natriuretic peptide, and the cardiac sodium channel. (grantome.com)
  • While CTCF is essential for embryonic development, little is known of its absolute requirement in somatic cells and the consequences of CTCF haploinsufficiency. (preprints.org)
  • To gain insight into the biochemical bases of the effects of stoichiometric imbalances, we explore the consequences of under- or over-expression of a subunit of a complex due, for instance, to a deletion, duplication or regulatory mutation of an allele encoding the relevant protein in a diploid organism. (biomedcentral.com)
  • Computer-based prediction methods can provide some insight into the potential consequences of these variants, but experimental techniques in cellular systems are crucial for confirming whether they are truly causal and for enabling a deeper understanding of their biological significance. (mpi.nl)
  • She completed her PhD in the lab of Angelika Amon at MIT, studying the causes and consequences of haploinsufficiency in yeast. (mit.edu)
  • CUL3 is a conserved protein of the Cullin family, comprising eight members, which contain a conserved cullin homology domain, named after its ability to select cellular proteins for degradation. (nature.com)
  • In the last several years, heterozygosity leading to haploinsufficiency for proteins involved in DNA repair pathways was shown to play a role in genomic instability and carcinogenesis after DNA damage is induced. (aacrjournals.org)
  • To address this issue, primary mouse cells, haploinsufficient for one or two proteins, ATM and RAD9, related to the cellular response to DNA damage were examined. (aacrjournals.org)
  • In the last few years, mounting evidence suggests that heterozygosity leading to haploinsufficiency for proteins involved in DNA repair pathways plays a role in genomic instability and carcinogenesis. (aacrjournals.org)
  • snRNAs naturally occur in human cells and are stabilized by endogenous cellular proteins. (locanabio.com)
  • While the molecular basis of this disease (C9-ALS/FTD) remains largely unknown, proposed disease mechanisms include C9orf72 loss of function due to haploinsufficiency, RNA gain of function (GOF) leading to protein sequestration and repeat-associated non-ATG (RAN) translation resulting in the production of toxic C9-RAN dipeptide repeat proteins. (neurodegenerationresearch.eu)
  • Somatic repeat expansion and/or age-related cellular stress results in titration of GGGGCC and GGCCCC RNA binding proteins followed by nucleocytoplasmic export of these RNAs and translation of highly toxic C9-RAN proteins in the cytoplasm that lead to neurodegeneration. (neurodegenerationresearch.eu)
  • Due to their positive charge, polyamines can interact with nucleic acids and proteins and regulate specific ion channels, thereby exerting wide-ranging effects on transcription, translation, RNA and protein stability and cell signaling (10). (ubatubasat.com)
  • are cellular structures that process the cell's genetic instructions to create proteins. (medlineplus.gov)
  • Autophagy is a cellular catabolic process that eliminates damaged cell organelles, unfolded proteins, and various intracellular pathogens through lysosomal degradation. (hindawi.com)
  • After the degradation of damaged proteins and lipids, amino acids and fatty acids are released into the cytoplasm and recycled for new biosynthesis of cellular components or energy production [ 4 ]. (hindawi.com)
  • The intact receptor lacks tyrosine kinase activity, but binding of GH and dimerization results in association with JAK2, a member of the Janus kinase family, which results in self-phosphorylation of the JAK2 and a cascade of phosphorylation of cellular proteins. (medscape.com)
  • The transcription factor NFκB mediates inflammatory responses which exert regulatory effects on bone homeostasis. (unc.edu)
  • A comparison of their known functions has identified, besides a common role within protein folding, multiple roles for the cyclophilins within pre-mRNA splicing and cellular signalling, and within transcription and cell cycle regulation for the parvulins. (biomedcentral.com)
  • According to this hypothesis, bidirectional sense and antisense C9orf72 transcription results in the recruitment of cellular factors to repeat expansion RNAs to produce sense and antisense RNA foci that sequester these toxic RNAs in the nucleus. (neurodegenerationresearch.eu)
  • Protein post-translational modifications (PTMs) take many shapes, have many effects and are necessary for cellular homeostasis. (biologists.com)
  • This Review summarizes the more recent biochemical, cellular and mouse model studies that underscore the importance of the ER acetylation process in maintaining protein homeostasis and autophagy within the secretory pathway, and its impact on developmental and age-associated diseases. (biologists.com)
  • A complementation assay using aco1-deficient yeast revealed a growth defect for the mutant ACO2 variant substantiating a pathogenic effect of the deletion. (huji.ac.il)
  • Because the effect of haploinsufficiency for one protein is relatively small, we hypothesize that predisposition to cancer could be a result of the additive effect of heterozygosity for two or more genes, critical for pathways that control DNA damage signaling, repair or apoptosis. (aacrjournals.org)
  • Animal models of polycystic kidney disease (PKD) have been invaluable in discovering and dissecting cellular and molecular pathways by which polycystic kidneys develop and by which progression of all types of PKD may be modified [ 1 ],[ 2 ]. (biomedcentral.com)
  • In my research, I mix cellular models, gene editing, and high throughput assays to find the determinants of penetrance in the development of PAH under these conditions. (stanford.edu)
  • Understanding the individual and combinatorial functional effects of these variants on cardiac sodium current in human cardiomyocytes can be an initial step in the stratification of ventricular arrhythmia risk to influence clinical decision making. (grantome.com)
  • Further, this work is highly innovative by providing a scalable approach to establish function of new candidate genetic variants, as well as to study the effects of such variants across multiple genetic backgrounds. (grantome.com)
  • CR exerts its effect by activating sirtuins 5 , 6 . (cellr4.org)
  • and to underpin the molecular, cellular, and circuit mechanisms whereby lithium acts through. (mcgill.ca)
  • They are non-immunogenic and can effect a wide variety of mechanisms to target RNA. (locanabio.com)
  • We will study the effects of genetic variation in Brugada syndrome on cardiac sodium channel expression in hopes to identify new mechanisms in Brugada syndrome and ultimately prevent SCD. (grantome.com)
  • Differential effects by sex with Kmt5b loss. (sfari.org)
  • We also tested the effect of KLF6 inhibition in HNSCC cell lines on proliferation and p21 expression. (mssm.edu)
  • Targeted stable reduction of KLF6 in HNSCC cell lines increased cellular proliferation while decreasing p21 expression. (mssm.edu)
  • We assess the effects on expression level, protein stability, intracellular localisation, interaction of the protein with other molecules, as well as using specific assays of protein function. (mpi.nl)
  • In this proposal, we will initially test the hypothesis that RNA GOF effects precede RAN protein accumulation by performing RNA-FISH, transcriptome analysis and immunological assays at various developmental periods and in different brain and spinal cord regions on asymptomatic, pre-symptomatic and symptomatic C9-BAC mice. (neurodegenerationresearch.eu)
  • The PHGDH gene is essential for the production of serine, which plays a central role in cellular metabolism," says Kevin Eade, PhD, a former Scripps Research postdoctoral associate who is a senior scientist at the Lowy Medical Research Institute. (scripps.edu)
  • This property stems from principles of cellular economy, but also, as explained below, as a requirement to avoid the formation of inactive sub-complexes when there is an imbalance in the concentration of one or several subunits. (biomedcentral.com)
  • However, the cellular determinants of NELL-1's bone-forming effects are still unknown. (nih.gov)
  • Conversely, rhNELL-1 systemic administration in mice showed a marked anabolic effect accompanied by increased numbers of Sca-1+CD45-CD31- bone marrow MPCs. (nih.gov)
  • Concepts regarding the effect of inflammation on osteogenesis during bone development remain elusive. (unc.edu)
  • The heterotopic bone formation approach using BMP2 was employed to assess bone formation potential in the mice with p65 haploinsufficiency in osteoprogenitors. (unc.edu)
  • Thus, even a small insulin-like effect of IGF-I could be more important than that of insulin itself, were it not for the IGFBPs that control the availability and activity of IGF-I. In fact, intravenous infusion of recombinant human IGF-I (rhIGF-I) can induce hypoglycemia, especially in the IGFBP3 deficient state. (medscape.com)
  • E3 ubiquitin ligases regulate cellular protein composition by providing target recognition and specificity to the ubiquitin-dependent proteasomal degradation pathway 12 . (nature.com)
  • Analysis of XY byg/byg gonads at 11.5 d post coitum reveals a growth deficit and a failure to support mesonephric cell migration, both early cellular processes normally associated with testis development. (plos.org)
  • Through genetic analyses and experiments in human-derived retinal tissue, we were able confirm that even a partial loss of PHGDH function can have a damaging effect on the retina. (scripps.edu)
  • GO Annotations consist of four mandatory components: a gene product, a term from one of the three Gene Ontology (GO) controlled vocabularies ( Molecular Function , Biological Process , and Cellular Component ), a reference, and an evidence code. (yeastgenome.org)
  • Currently, multiple clinical studies investigating the therapeutic effects of the irreversible ODC inhibitor 2-difluoromethylornithine (DFMO) on neuroblastoma, astroglioma and other cancers are underway (16C18). (ubatubasat.com)
  • We propose a haploinsufficiency model in which reduced levels of wild-type caveolin-3, although not rendered dysfunctional due to the caveolin-3 R26Q mutant protein, are insufficient for normal muscle cell function. (elsevierpure.com)
  • 2022. Behavioural and molecular characterisation of the Dlg2 haploinsufficiency rat model of genetic risk for psychiatric disorder . (cardiff.ac.uk)
  • Event-free survival (death or transplantation) was shorter in the T-BOX group (P = 0.022), although age had a significant effect in the hazard model (P = 0.0461). (stanford.edu)
  • The buffer effect also appears in higher-order structures provided that there are intermediate subcomplexes in the assembly process. (biomedcentral.com)
  • The expression and cellular localization of HERG protein were studied with Western blot and immunofluorescence methods. (elsevierpure.com)
  • NK cells are specialized effectors of the innate immune system that destroy their targets by antibody-dependent cell-mediated cytotoxicity, have prominent antitumor effects, and are potent killers of virally infected cells. (medscape.com)
  • In this review we discuss the role of NAD + as main substrate for the beneficial effect mediated by sirtuins and PARP and its potential role to develop strategies to prevent aging. (cellr4.org)
  • For instance, if the complex is a trimer that contains 2 molecules of A and one molecule of B, the effect of a decrease in the concentration of A is probably more dramatic than for B, as shown in Fig. 1 . (biomedcentral.com)
  • In mouse, constitutive Cul3 haploinsufficiency leads to motor coordination deficits as well as ASD-relevant social and cognitive impairments. (nature.com)
  • Recruit endogenous ADARs (adenosine deaminases acting on RNA) to effect A to I (G) RNA editing. (locanabio.com)